Lung Biopsy Interpretation
Case 1 -
Usual Interstitial Pneumonia (UIP)
Anna-Luise A. Katzenstein & Jeffrey L. Myers
This 73 year old man complained of increasing dyspnea and dry cough for two years. He currently is
unable to walk more than a few feet without becoming dyspneic. Rales were noted bilaterally on physical
examination and there was evidence of early clubbing. Pulmonary function tests showed severe restrictive
defects. Chest x-ray and CT showed bilateral interstitial reticular opacities worse at the bases with
foci of subpleural honey-comb change. An open lung biopsy was performed.
Case 1 - Figure 1 - Low magnification view showing an interstitial process with distinctly non-uniform appearance. There are alternating zones of alveolar septal fibrosis, inflammation and normal lung.
Case 1 - Figure 2 - Another area from the same slide composed of end-stage, honey-comb lung.
Case 1 - Figure 3 - The area in this photo contains prominent interstitial inflammation and fibrosis within which a small, well-delineated, lightly staining fibroblast focus is visible.
Case 1 - Figure 4 - Higher magnification of fibroblast focus shown in Figure 3. This lesion is an aggregate of oval to spindle-shaped fibroblasts and myofibroblasts arranged with their long axes parallel to the long axis of the alveolar septum. They are embedded in lightly staining, myxoid appearing stroma.
This slide shows extensive interstitial scarring composed of dense collagen deposition and associated
mild chronic inflammation. Areas of microscopic honey-comb change are prominent and are characterized by
enlarged airspaces lined mainly by bronchiolar epithelium and filled with a mucinous and proteinaceous
exudate containing varying numbers of inflammatory cells. The changes have a strikingly heterogeneous,
non-uniform appearance at low magnification with islands of relatively normal lung interspersed among the
abnormal fibrotic zones. Small areas of active fibrosis (fibroblast foci)
are also seen along the interstitium. These foci are composed of spindle-shaped fibroblasts and
myofibroblasts within lightly staining, myxoid appearing stroma arranged with their long axis parallel to
the long axis of the alveolar septa. The finding of fibroblast foci in a background of inactive
appearing collagen type fibrosis indicates temporal heterogeneity.
The current classification of the idiopathic interstitial pneumonias includes four entities outlined
in Table 1, and the main clinical and pathologic features of these diseases are contrasted in Tables 2
and 3. UIP is the most common idiopathic interstitial pneumonia, comprising over 60% of cases, and idiopathic pulmonary fibrosis (IPF) and cryptogenic fibrosing
alveolitis (CFA) are synonyms for this disease. The importance of this classification is to
separate the acute (AIP) and the chronic interstitial pneumonias, and in the latter group to separate the
poor prognosis (UIP) from the good prognosis (DIP, NSIP) diseases. The possibility that interferon gamma
may be beneficial in UIP cases, as well as the development of new therapeutic agents aimed at stopping
the fibrosing process, has added additional impetus to precisely classify these entities.
The histologic classification of the idiopathic interstitial pneumonias is usually straightforward.
UIP is recognized by a temporally and spatially variegated interstitial fibrosing process. Spatial
variegation is recognized at low magnification by a patchwork arrangement of interstitial collagen-type
fibrosis, fibroblast foci, interstitial inflammation, microscopic honey-comb change, and normal lung.
Architectural distortion typified by honey-comb change or interstitial scarring or both is usually a
prominent feature. Temporal variegation is characterized by the presence of active, on-going areas of
fibrosis (fibroblast foci) in a background of old, inactive fibrosis
(collagen and honey-comb areas). That is, there is evidence of active ongoing disease as well as
inactive scarring from previous disease. Fibroblast foci represent microscopic areas of acute lung
injury, and they are the earliest histologic manifestation of UIP. The pathogenesis UIP appears to be
related to the occurrence of these microscopic foci of acute lung injury in widely scattered portions of
lung over many years.
Clinically, UIP usually affects middle aged to older adults, and the disease is uncommon under the age
of 40. Men are affected about twice as often as women. The onset is insidious with dry cough and
gradually increasing shortness of breath, and the course is relentlessly progressive with death due to
respiratory failure occurring in most patients after 2 to 5 years. There is no known effective therapy,
although promising results have been described recently with interferon gamma.
The main lesion in the differential diagnosis of UIP is the fibrosing variant of NSIP. The two main
histologic features that separate UIP from fibrotic NSIP include the presence of a patchwork pattern of
parenchymal involvement and significant architectural distortion. Interestingly, small foci resembling
NSIP (so-called NSIP-like areas) are commonly found in otherwise typical UIP cases (a situation analogous
to DIP-like areas in UIP), and, therefore, in order to diagnose NSIP the process should be uniform
everywhere with little if any architectural distortion.
The following are helpful guidelines in evaluating the idiopathic interstitial pneumonias:
| Be cautious about diagnosing UIP when|
| || the patient is under 40 years old|
| || microscopic honey-comb change is absent|
| || inflammation is prominent microscopically|
| Do not diagnose NSIP when significant architectural distortion is present|
| Use the clinical history to avoid mistakes|
| || the presence of a radiographically localized infiltrate excludes UIP and other idiopathic interstitial pneumonias|
| || rapid (within days) course and systemic symptoms (fever) exclude UIP|
| || active fibroblast proliferation in patients who are not on a ventilator probably is not AIP (consider BOOP)|
| Not all lung biopsy specimens will be classifiable into one of the 4 idiopathic interstitial pneumonias. Cases composed entirely of end-stage fibrotic or honey-comb lung should be diagnosed descriptively rather than attempting to pigeon-hole them into a specific category.|
Table 1. Classification of Idiopathic Interstitial Pneumonia
| Usual Interstitial Pneumonia (UIP)|
| Desquamative Interstitial Pneumonia (DIP)/Respiratory Bronchiolitis|
| Interstitial Lung Disease (RBILD)|
| Acute Interstitial Pneumonia (AIP, Hamman-Rich disease)|
| Non-Specific Interstitial Pneumonia (NSIP)|
Table 2. Contrasting Clinical Features of the Idiopathic Interstitial
| ||UIP* ||DIP/RBILD** ||AIP*** ||NSIP****|
|Male/Female ||2.1/1 ||1.75/1 ||1/1 ||1/1.3|
|Average Age (Range) ||57 (27-77) ||45 (16-75), DIP36 (22-53), RBILD ||49 (7-77) ||52 (9-78)|
|Onset ||Insidious ||Insidious ||Acute ||Insidious / Subacute|
|Fever|| No ||No ||Common|| Common|
|HRCT ||Bilateral reticular opacities, peripheral and basilar predom- inance, subpleural honeycombing ||Ground glass opacity, lower lung and subpleural, irregular lines ||Air-space consolidation and ground glass opacity ||Ground glass opacity, usually lower lobes|
|Course ||Slowly progressive ||Chronic ||Fulminant (1 to 2 months) ||Chronic to subacute|
|Outcome ||71% (51-93%) mortality ||27% mortality (DIP), 0% mortality (RBILD) ||62% (50-88%) mortality ||12.5% (0- 29%) mortality §|
* Data from Crystal, Carrington, Katzenstein (1986), Guerry-Force, Wells, Cherniack,
Bjoraker, Daniil, Nagai, Travis, Flaherty (2002)
** Data from Liebow (1965), Gaensler, Patchefsky, Tubbs, Carrington, Myers (1987),
Yousem, Travis, Flaherty (2002)
*** Data from Katzenstein (1986), Olsen, Primack
**** Data from Katzenstein (1994), Park, Bjoraker, Daniil, Nagai, Cottin, Flaherty (2002)
§ Mortality rates are the average of reported mortality rates in major series (range of
reported rates in parenthesis). The results of Travis et al's and Nicholson et al's series are not
included because they appear to lump UIP cases with fibrotic NSIP cases, and the subsequent mortality
rates are considerably higher than other series (35% 10 year survival and 45% 5 year survival,
Table 3. Contrasting Pathologic Features of the Idiopathic Interstitial
| ||UIP ||DIP/RBILD ||AIP ||NSIP|
|Distribution of changes ||Patchy, non-uniform (patch-work pattern) ||Diffuse (DIP)/ patchy(RBILD), uniform ||Diffuse, uniform ||Diffuse, uniform|
|Temporal appearance ||Variegated ||Uniform ||Uniform ||Uniform|
|Alveolar septal inflammation ||Scant, patchy ||Scant ||Scant ||Prominent|
|Collagen type fibrosis ||Characteristic, patchy ||Variable, diffuse ||Absent ||Variable, diffuse|
|Fibroblast proliferation ||Fibroblast foci ||Absent ||Diffuse ||Rare fibroblast foci|
|Intraalveolar macrophage accumulation ||Occasional, focal ||Diffuse (DIP) or peribronchiolar (RBILD) ||No ||Occasional, focal|
|Microscopic honey- comb change ||Characteristic ||Usually absent ||No ||Usually absent|
|Hyaline membranes ||Absent ||Absent ||Occasional, focal ||Absent|
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